Nicotinamide phosphoribosyltransferase inhibits receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation in vitro.
Nicotinamide phosphoribosyltransferase inhibits receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation in vitro.
复制标题
DOI：
10.3892/mmr.2016.6069
复制
发表时间：
2017-02
影响因子：
3.4
通讯作者：
Kim JY
中科院分区：
文献类型：
--
作者：
Baek JM;Ahn SJ;Cheon YH;Lee MS;Oh J;Kim JY
脂肪因子烟酰胺磷酸核糖基转移酶(NAMPT)，又称前B细胞集落增强因子或胰岛素样激素Visfatin，在辅酶烟酰胺腺嘌呤二核苷酸的生物合成过程中，在烟酰胺向烟酰胺单核苷酸的转化中起着至关重要的作用。已有报道证实NAMPT对人外周血单核细胞和CD14+单核细胞的破骨细胞形成有抑制作用。然而，NAMPT对骨髓巨噬细胞(BMM)来源的破骨细胞分化的影响及其在该过程中的确切作用仍不清楚。以重组NAMPT和骨髓基质细胞为破骨前体的体外研究表明，NAMPT通过抑制多种早期信号转导通路的磷酸化而抑制核因子-κB配体受体激活剂(RANKL)诱导的破骨细胞生成，这些信号转导通路包括c-jun氨基末端激酶、Akt、糖原合成酶-3β、Bruton‘s酪氨酸激酶和磷脂酶Cγ-2。此外，免疫印迹和逆转录定量聚合酶链式反应分析表明，NAMPT下调活化的T细胞胞浆中c-Fos和核因子的mRNA和蛋白表达水平，导致破骨细胞特异性基因的表达减少，包括抗酒石酸酸性磷酸酶、破骨细胞相关受体和组织蛋白K。然而，NAMPT处理的成熟破骨细胞的骨吸收活性与未处理的对照破骨细胞相似。这一发现表明，NAMPT通过靶向破骨细胞前体细胞而不是成熟的破骨细胞来发挥其抗破骨细胞活性。因此，本研究表明，NAMPT在RANKL介导的骨髓基质细胞向破骨细胞分化过程中起负调控作用，为治疗骨质疏松等骨相关疾病提供了潜在的治疗靶点。
The adipokine nicotinamide phosphoribosyltransferase (Nampt), also known as pre-B-cell colony-enhancing factor or the insulin-mimetic hormone visfatin, has a crucial role in the conversion of nicotinamide to nicotinamide mononucleotide during biosynthesis of the coenzyme nicotinamide adenine dinucleotide. Previous reports have demonstrated the inhibitory effects of Nampt on osteoclast formation from human peripheral blood mononuclear cells and CD14+ monocytes. However, the effects of Nampt on bone marrow macrophage (BMM)-derived osteoclastogenesis and its precise role in the process remain unclear. The present in vitro study used recombinant Nampt and BMMs as osteoclast precursors demonstrated that Nampt suppresses receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis by decreasing the phosphorylation of various early signal transducers, including c-Jun N-terminal kinase, Akt, glycogen synthase kinase-3 β, Bruton's tyrosine kinase and phospholipase C γ-2. In addition, western blotting and reverse transcription-quantitative polymerase chain reaction analysis indicated that Nampt downregulates the mRNA and protein expression levels of c-Fos and nuclear factor of activated T cells, cytoplasmic 1, leading to a decrease in the expression of osteoclast-specific genes including tartrate-resistant acid phosphatase, osteoclast-associated receptor and cathepsin K. However, the bone-resorbing activity of mature osteoclasts treated with Nampt was similar to untreated control osteoclasts. This finding indicates that Nampt exerts its anti-osteoclastogenic activity by targeting osteoclast precursor cells rather than mature osteoclasts. Consequently, the present study demonstrated that Nampt acts as a negative regulator of RANKL-mediated differentiation of BMMs into osteoclasts, suggesting the potential therapeutic targets to treat bone-related disorders such as osteoporosis.